Journal of Molecular Liquids 358 (2022) 119210

Contents lists available at ScienceDirect

Journal of Molecular Liquids

journal homepage: www.elsevier.com/locate/molliq

A simulation study of an applied approach to enhance drug recovery

through electromembrane extraction
Mohammad Khosravikia a, Ahmad Rahbar-Kelishami b,⇑
a
School of Chemical Engineering, College of Engineering, University of Tehran, Tehran 14179-35840, Iran
b
Research Lab for Advanced Separation Processes, Department of Chemical Engineering, Iran University of Science and Technology, Narmak, Tehran 16846-13114, Iran

a r t i c l e i n f o a b s t r a c t

Article history: In pharmaceutical workflows, sample preparation is a crucial step. In today’s world, microextraction is
Received 8 January 2022 very popular because it allows for faster and cheaper analyses. By using an electric field to drive charged
Revised 16 April 2022 species to migrate across the membrane, electromembrane extraction is an alternative to liquid-phase
Accepted 19 April 2022
microextraction. The applied voltage in the EME system causes ionizable compounds to be transported
Available online 25 April 2022
from an aqueous sample solution across a supported liquid membrane (SLM) into an acceptor phase.
This study employs a numerical method (finite element method) to obtain solutions to the Poisson
Keywords:
and Nernst-Planck equations to analyse the transfer of acidic and basic drugs components in electromem-
Supported liquid membrane
Nernst-Planck-Poisson equations
brane extraction. Initially, we considered similar properties in hollow fiber membrane and donor/accep-
Electromembrane extraction tor solution to solve the governing equations. In the next step, the effect of parameters such as applied
Sample preparation voltage, pH donor/acceptor phase, membrane thickness, initial drug concentration, extraction time, the
Basic drugs diffusion coefficient of the drug species and membrane porosity on the performance of electromembrane
Partitioning effect extraction were studied by applying partitioning conditions. The most important result of this study is
that the flux was strongly dependent on the potential difference over the SLM, and increased potential
difference increased the flux. For instance, by increasing the applied voltage from 5 V to 30 V, the recovery
extraction increased from 40% to 100. It was also realized that upon applying an donor phase pH of
pHd ¼ 2, the extraction recovery reaches a value of 98%. The findings of this study can help better under-
stand the EME system to find suitable conditions to enhance drug extraction.
Ó 2022 Elsevier B.V. All rights reserved.

1. Introduction turizing extraction methods for more environmentally friendly

Over the years, pharmaceutical products have played an essen-
tial role in human health [1–3]. During the drug production pro-
cess, it is crucial to conduct chemical analysis of the drugs
because it guarantees the quality, safety, and efficacy of the drugs
produced and that is why it is of great significance to the pharma-
ceutical industry [4–6]. The chemical analysis process begins with
sample preparation and extraction, which are among the most
basic steps. They consume more than 80% of the time [7,8]. During
the development of analytical instruments, sensitivity and selec-
tivity have greatly improved in the field of analytical chemistry.
Nevertheless, analyzing complex samples directly remains a chal-
lenge [9]. As a result, considerable research efforts are directed at
improving and developing sample preparation procedures
[10,11]. Accordingly, particular attention has been paid to minia-
⇑ Corresponding author.
E-mail addresses: mkhosravikia@ut.ac.ir (M. Khosravikia), ahmadrahbar@iust.ac.
ir (A. Rahbar-Kelishami).
and green techniques, demanding fewer organic solvents and sam-
ples [12].
Sample extraction methods such as liquid–liquid extraction
(LLE) [7,13], and solid-phase extraction (SPE) have a lengthy anal-
ysis time [14]. On the other hand, the large volume of the sample
and the need for a significant amount of solvent pose a potential
threat to humans and the environment [15]. Therefore, it has been
replaced by new microextraction methods such as solid phase
(SPME) [16–19], single drop (SDME) [20,21], and hollow fiber liq-
uid phase (HF-LPME) [22–24]. All microextraction methods have
been attended to by researchers for their simplicity, low sample
size, high speeds, environmental compatibility, reproducibility,
low solvent consumption, and automation capabilities [25,26]. In
terms of microextraction methods, hollow fiber liquid-phase
microextraction is more practical due to its high porosity, improv-
ing surface area and maximizing extraction efficiency [27,28]. In
another perspective, electromembrane extraction (EME) is a
method of LPME that relies on the migration of charged species
under an electric field [29]. A voltage applied in the EME system

https://doi.org/10.1016/j.molliq.2022.119210
0167-7322/Ó 2022 Elsevier B.V. All rights reserved.
M. Khosravikia and A. Rahbar-Kelishami
facilitates the translocation of ionizable compounds from aqueous
solutions across supported liquid membranes (SLM) into an accep-
tor solution [30,31]. Thus, due to the advantages of HF-LPME and
EME techniques, the extraction rate of the drug species can be sig-
nificantly increased by combining them.
In this method, hollow fiber impregnated with organic solvent
is used as the interface between the acceptor and donor phase
located in the aqueous phase, which is extracted at a higher speed
by placing the electrode and applying the electric potential differ-
ence [32–35]. This method is efficient due to its high operating
speed and is used in various fields such as the extraction of chem-
ical and food dyes [36], pharmaceuticals [12,37,38], heavy metals
[39], organic and inorganic anions [40,41]. Using this technique,
considerable experimental and theoretical studies have been per-
formed to extract basic and acidic compounds from water, plasma,
urine, whole blood, and breast milk. Among the experimental stud-
ies, for the first time in 2006, Pedersen-Bjergaard and Rasmussen
proposed an electromembrane extraction method to increase the
extraction rate as a subset of micro-liquid phase extraction meth-
ods with hollow fiber [42]. They showed that drug recovery
increased to about 79% by applying high voltage.
Yu et al. [43], studied the effect of extraction time and voltage
on antipsychotic drugs such as chlorprothixene, haloperidol, and
risperidone by electromembrane extraction from blood and urine
samples. They found that, the optimal extraction times and applied
voltage for blood and urine samples are 30, 20 min and 60 V,
respectively. The recovery rate in optimal conditions for all three
drugs was 74 to 100%, indicating the successful extraction of drugs
by the EME method. In another study by Rahimi et al. [44], to
extract propranolol, diltiazem and lidocaine, a hollow fiber
polypropylene membrane with a thickness of 300 lm and a length
of 30 mm was used. In this study, the outer wall of the membrane
is impregnated with a 1-octanol organic solution to fill the mem-
brane cavities. Then the sample solution is filled into the fibers
with a syringe at a 2 ml /min rate, and a syringe head is closed
by mechanical pressure and heat. The membrane is placed inside
the HCL acceptor solution. By applying a voltage of 100 V through
the platinum wire, in a short time, the extraction recovery was in
the range of 65–88% for all drug samples.
Most studies have used the electromembrane extraction
method to separate various compounds from biological fluids,
while Bolvince et al. [45], were the first to study the effect of
EME on the separation of drug compounds from complex animal
semi-solid tissues. Above 65% drug recovery, very low matrix
effects and low phospholipid content indicate the high effective-
ness of this approach in purifying rabbit tissue samples. The
method of gel electromembrane extraction with a rotating elec-
trode to separate Naloxone, Naltrexone and Nalbuphine from
human urine samples was studied by Behpour et al., [46]. In this
study, the parameters of applied voltage, pH of donor and acceptor
phase, electrode rotation speed and extraction time have been
studied as parameters affecting separation. In this new method,
the problem of reducing the mass transfer rate due to the forma-
tion of a layer of analyte on the membrane with the presence of
a rotating electrode is solved, and the thickness of the Nernst dif-
fusion layer is reduced. Therefore, this method is more effective
and efficient than other electromembrane methods with fixed elec-
trodes for the extraction process [47].
The lack of theories to elucidate the mass transport phe-
nomenon in confined space severely restricted the development
of EME for different applications, and a new set of theories that
can more accurately describe the HF-EME effect are urgently
needed [48,49]. Hence the dominant mechanisms of crime transfer
behaviour must be identified, and given the economic and environ-
mental constraints, mathematical modelling is a valuable tool for
this purpose.
2
Journal of Molecular Liquids 358 (2022) 119210
Gjelstad et al. [50], first proposed a theoretical model derived
from the Nernst-Planck equation to describe the amount of flux
passing through the SLM membrane. In this study, the effect of
parameters such as the magnitude of the electric potential differ-
ence, the system’s ionic equilibrium, and the absolute temperature
on the flux has been investigated. The results of this study are con-
firmed by data from experimental work on five drug samples.
Despite examining a number of parameters to understand the phe-
nomenon better, there was no prediction for extraction time or
recovery due to the lack of time-dependent effects in the model.
In another study by Gjelstad et al. [51], in addition to an experi-
mental study, a mathematical model was presented to investigate
the extraction kinetics in hollow fiber liquid-phase microextrac-
tion systems and electromembrane by several drugs. The main
assumptions in this model are: (1) replacement of the transfer in
the membrane by diffusion and taking into account the delay time
in extraction, which is determined by the retention time of the
analyte in the membrane, (2) selection of mass transfer through
the membrane as a determining step velocity, and (3) due to the
presence of a stirrer in the sample solution, mass transfer at this
stage is not considered a limiting factor.
Hansen et al. [52], modified the proposed model to study the
effect of ion balance on the extraction kinetics and the rate of
steady state recovery in the electromembrane extraction method.
Based on the results, the effect of ionic balance in the range of
0.01–10 on the rate of extraction recovery for all 12 drug samples
is very small and negligible. This study showed that the effects of
ion balance on the extraction rate mentioned in the previous work
are expired and may be due to other mechanisms such as pH
effects and ion-pair formation. Restan et al. [53], proposed a theo-
retical model to investigate the effect of pH on electromembrane
extraction efficiency. A theoretical model to describe the process
of extraction and distribution of analytes in the EME system as a
function of time was presented by Seip et al [54]. This model is
based on practical experiments on drugs and peptides that, except
in rare cases, well describe the distribution behavior. The proposed
model showed that the EME system behaves like a voltage distri-
bution system.
This study employs a numerical method (finite element
method) to obtain solutions to the Poisson and Nernst-Planck
equations to analyse the transfer of acidic and basic drugs compo-
nents in electromembrane extraction. Initially, we considered sim-
ilar properties in hollow fiber membrane and donor/acceptor
solution to solve the governing equations. In the next step, the
effect of parameters such as applied voltage, pH donor/acceptor
phase, membrane thickness, initial drug concentration, extraction
time, the diffusion coefficient of the drug species and membrane
porosity on the performance of electromembrane extraction were
studied by applying partitioning conditions. Elections were calcu-
lated based on the drug concentration distribution, and an elec-
trokinetic process was identified and described.
2. Theory and problem formulation
The electromembrane extraction principle (EME) is illustrated
in Fig. 1. Through an SLM containing an organic solvent (i.e., 1-
octanol or) immobilized in a porous hollow fiber, drug species ana-
lytes are extracted from a sample solution (donor phase) and deliv-
ered to an acceptor phase. In order for the EME to work, a voltage is
applied over the SLM that is produced by a power supply. It should
be noted that HCl is used in the acceptor phase to improve the pro-
cess. At unsteady-state conditions, EME displays selectivity, rectifi-
cation, and concentration polarization electrokinetic phenomena.
It is assumed that the hollow fiber membrane which is used as
SLM in the EME is dense; it, therefore, follows that while the per-
M. Khosravikia and A. Rahbar-Kelishami
Fig. 1. Schematic diagram of the electromembrane extraction system with hollow fiber, electrodes, and power supply. The zoom section represents extraction of positively
charged drugs.
mittivity, fluid viscosity, and diffusivity of the solution in the
donor/acceptor phase are assumed to be uniform throughout, they
must also be viewed as different from those of the SLM [35,41].
As the distribution and permeability of charged analytes con-
tribute to high selectivity and mass transfer within the SLM, they
play a significant role in extraction recovery. For this purpose,
the log P parameter is used, representing a measure of polarity.
Note that if log P > 2, the drug is nonpolar, if 1 < log P < 2, the drug
is medium-polar, and if log P < 1, the drug is polar. Additionally,
Hydrogen bond interactions have been hypothesized as the pri-
mary mechanism of solvation of protonated basic substances
ðlog P > 1:5Þ, and successful SLM solvents (including NPOE) for
such analytes all have (i) high hydrogen bond basicity, (ii) almost
zero hydrogen bond acidity, and (iii) 3 < log P < 5:5 [55]. As indi-
cated in Fig. 2a, all drugs used in this study have low polarity. In
addition, changes in charges drug relative to pH are shown in
Fig. 2b.
Strategies used to control drug delivery from therapeutic sys-
tems are based on biological, physicochemical and mathematical
principles, which can modify and control the temporal and spatial
drug release profile. There are many mechanisms by which the
drug release can be controlled in a system: dissolution, diffusion,
osmosis, partitioning, swelling, erosion, and targeting. They are
dependent on the particular application and may act simultane-
ously or at different stages of a process of delivery. It is common
for a system or device to present more than one of them, but the
classification of the mechanism of release is based on the main
mechanism [56].
To solve the problem in question, it was assumed that the sys-
tem is in unsteady-state condition and, as mentioned earlier, the
flow regime is laminar (creeping flow), and the electrolyte is HCl
solution, which is a Newtonian and incompressible fluid. Mean-
while, it was considered; the diffusion coefficient of any ion in
the solution (donor/acceptor phase) Df;j and in the SLM Dm;j

 
(j ¼ 1 for cations Hþ , j ¼ 2 for anions ðCl Þ, and j ¼ 3 for drugÞ
3
Journal of Molecular Liquids 358 (2022) 119210
the fluid permittivity ef and the SLM permittivity em , and / and cj
represent the electric potential, and flux of ionic species, respec-
tively. The phenomenon will be formulated using the modified
Poisson-Nernst-Planck equations as follows [35]:
(
ef r2 / ¼ qv i ¼ 0
ð1Þ
em r2 / ¼ qv i ¼ 1
8  
> @ci Z ec
< @t
þ r  cj u  Df;j rcj  Df;j kjB Tj r/ ¼ 0i ¼ 0
  ð2Þ
>
: @c i
Z ec
þ r  cj u  Dm;j rcj  Dm;j kjB Tj r/ ¼ 0i ¼ 1
@t
In the above equations, the ionic density of the electrolyte is
P
defined as qE ¼ 2j¼1 zj Fcj where zj and cj are the charges and con-
centrations of ionic species in the donor/acceptor phase, respec-
tively. The parameters F, R, e, and T denote the Faraday
constant, the universal gas constant, the charge of electron, and
the absolute temperature of the system, respectively. The term i
stands for a step function that is equal to ‘‘zero” and ‘‘one” outside
and inside the SLM, respectively. The fluid velocity is considered by
u in this work, which is not the case here. Further, the deforma-
tions of the SLM have been neglected for simplicity.
The effective diffusion coefficient of the SLM is found through

the following relation in terms of its porosity e and tortuosity s
[57]:

e
Dm;i ¼ xDf;i ¼ D ð3Þ
s f;i
SLM’s diffusivity and transport capability decrease as this ratio
decreases, i.e., a lower extraction recovery. The diffusion coeffi-
cients in the SLM decrease with an increased concentration of ana-
lyte ions. Thus, with continued processing, the membrane’s
efficiency will decrease. It would be reasonable to assume for x
a monotonically decreasing function so as to account for the effect
on the diffusion coefficient of the ions. In practical problems, this
M. Khosravikia and A. Rahbar-Kelishami Journal of Molecular Liquids 358 (2022) 119210

Fig. 2. (a) Chemical structure for the drugs used in this work; (b) impact of pH on drug charges.

relation helps us to respond appropriately to the nonlinear diffu- Table 1

sion phenomena across the SLM. In the present study, we assume Boundary conditions considered for the computational region illustrated in Fig. 2b.
that the SLM maintains the same capabilities throughout the Surface Electrical potential (Eq. (1)) mass transfer (Eq. (2))
extraction process. In addition, the pH of the donor and acceptor X1 Constant voltage bias / ¼ Vapp Ion-impervious
phases may change throughout the extraction process. pH changes n:Nj ¼ 0
are not as significant in most cases because buffers are used to pre- X2 Grounded / ¼ 0 Ion-impervious
vent them. In this way, it can be presumed that pH remains almost n:Nj ¼ 0
constant. X3 Insulation n:r/ ¼ 0 Ion-impervious
n:Nj ¼ 0
The boundary conditions assumed for Eqs. (1) and (2) are given
X4 Charged continuous at the SLM– Partitioning condition
in Table 1 and shown in Fig. 3b. electrolyte interface Pi;d ¼
ci;m
ci;d
It is noted that, the Pi is represented the partitioning coefficient
X5 Partitioning condition
and is defined as the ratio of the interfacial ionic concentrations Pi;a ¼
ci;m
ci;a
inside and outside the SLM. Hydrophobicity or hydrophilicity of
an analyte is represented by this parameter. Partition coefficients
are useful in estimating the distribution of drugs within the body,
as it gives a measure of a solute’s hydrophobicity and a proxy for the partition coefficient measures how hydrophilic (‘‘water-
loving”) or hydrophobic (‘‘water-fearing”) a chemical substance
its membrane permeability. Most commonly, one of the solvents
is water, while the second is hydrophobic, such as 1-octanol. Hence is. Partition coefficients are useful in estimating the distribution

4
M. Khosravikia and A. Rahbar-Kelishami
Fig. 3. (a) 2-D view of the EME including the donor/acceptor phase, SLM and the geometric parametersthe; (b) schematic of EME with coordinate system and the boundary
conditions applied in simulation. The EME has the length LN , the donor thickness W d , the acceptor thickness Wa , and the SLM thickness W s Furthermore, the EME tank filled
with aqueous HCl solutions.
of drugs within the body. Due to the possibility of different pH’s
between donor and acceptor solutions and the fact that the parti-
tion coefficient is highly dependent on the pH, different partition
coefficients for the left and right walls of the SLM should be
assumed. As it was remarked previously, the permittivity, the dif-
fusivity, and the dynamic viscosity are considered different inside
and outside the SLM. From another point of view, the partitioning
of ions happens at the SLM-electrolyte interface, for instance, due
to variations in the electrostatic or van der Waals interaction forces
of ions. One well-known phenomenon, i.e., variations in the elec-
trostatic self-energies of ions occurring due to the permittivity dif-
ference, the so-called Born energy, is taken into account here [35].
The extraction recovery, Rð%Þ, for any analyte is calculated as
follow:
  
na;final Va ca;final
Rð%Þ ¼  100 ¼  100
nd;initial Vd cd;initial
where nd;initial and na;final are the numbers of analyte moles initially
present in the donor solution and the number of analyte moles
finally collected in the acceptor solution, respectively. V a is the vol-
ume of the acceptor phase, V d is the donor volume, ca;final is the final
analyte concentration in the acceptor phase, and cd;initial is the initial
analyte concentration within the donor.
3. Solution method
Given that Eqs. (1) and (2) are interdependent and highly non-
linear; one should use appropriate numerical tools to solve them.
Here, the equations were solved using Comsol Multiphysics soft-
ware (5.6a), which works based on the high-performance finite
element method. Electrostatic, and Transport of Diluted Species
physics was used to simulate the present system using a combina-
tion of triangular and square meshes. A mesh-independent study
was conducted to determine the number of meshes needed for
receiving mesh-independent outcomes. The results of the mesh-
independent study indicate that utilizing 83,000 mesh elements
for EME is acceptable to get mesh-independent results (below
0.1% discrepancy as compared with those obtained utilizing
120,000 mesh elements). As an example, a mesh element in a
EME is shown in Fig. S1 (please see supplamentary information
file). To verify the validity of the model developed, the results of
Journal of Molecular Liquids 358 (2022) 119210
EME system were successfully compared with the data of Tehrani
et al.[58] (Fig. S2, please see Supplementary Information).
4. Results and discussions
In the present study, electrokinetic basic drugs transport vari-
ables and mass transfer in electromembrane extraction setup have
been studied. The effective variables that have been investigated
include the electrolyte bulk concentration, thickness of SLM,
applied voltage, pH of donor/acceptor phase, and differences in dif-
fusivity of the bulk solution and SLM. Values of parameters and
variables used in the simulation process are given in Table S1.
Depending on the nature of the acidic or basic drug, the EME can
be selective towards particular ionic species. The EME in this study
are selective towards cations due to the nature of the drug being
ð4Þ basic [35]. An important point to remember is that in EME study
uses a stirrer mixed to ensure effective convection in the donor
solution and speed up the extraction process. In other words, stir-
ring dramatically speeds up the ion transport in the sample, while
the time-consuming aspect implicates transporting ions across the
SLM, acceptor solution, and only nearby media in the sample solu-
tion. In order to solve this problem, we used a more significant dif-
fusion coefficient for the analyte in the donor phase, which results
in the modelling has been able to generate a uniform distribution
of the ions over the donor solution.
Fig. 4 shows EME process time’s effect on the recovery of drug
extraction under Vapp ¼ 20 V, pHd ¼ 5, pHa ¼ 2, CD ¼ 3 ppm,
DD ¼ 1e  11 m2 =s, and T ¼ 298:15 K conditions for haloperidol,
methadone, nortriptyline, loperamide, and pethidine drugs. This
was simulated with five basic drug substances (chemical struc-
tures depicted in Fig. 3a). An important parameter of EME is the
extraction time since it determines how many analytes are
extracted from the donor phase. EME is known as a rapid and
high-efficiency method. When the voltage 20 V was applied on
the EME setup, the recoveries improved with increasing extraction
time up to 8 min for most analytes. As indicated in Fig. 4, after
15 min, the electromembrane extraction process has reached a
steady state, and the significant extraction has taken place in less
than 10 min, indicating the high efficiency of the EME method.
The distribution ratio of pethidine resulted in a long steady-state
extraction time, exceeding 15 min due to its low potency. (please
see Fig. 3b). It should be remarked that the recovery rates for four
5
M. Khosravikia and A. Rahbar-Kelishami Journal of Molecular Liquids 358 (2022) 119210

Fig. 4. Extraction recovery vs. extraction time at Vapp ¼ 20 V, and 10 mM HCl in the
acceptor solution.

of the model compounds were greater than 80% after just 5 min of
extraction.
From another point of view, typically, extraction time is essen-
tial in optimizing the energy and cost of the extraction process. The
drug contents were kept to be the not considerable difference after
30 min extraction time. This phenomenon could be described by
Fick’s second law of diffusion, indicating that final equilibrium will
be reached between the bulk concentrations in the SLM and solu-
tion after a particular time [59].
The effect of applied voltage on extraction recovery in the
pHd ¼ 5, pHa ¼ 2, CD ¼ 3 ppm, DD ¼ 1e  11 m2 =s, and
T ¼ 298:15 K conditions is shown in Fig. 5. EME is based on the
electromigration of charged analytes through an electric field.
According to the Nernst–Planck equation, the applied voltage influ-
ences the ionic transfer across the SLM. The importance of applied
voltage can affect the flux of drugs through the membrane as the
Fig. 5. (a) Extraction recovery vs. extraction time for nortriptyline at different
power of the electric field depends on the applied voltage
voltages, and 10 mM HCl in the acceptor solution, and (b) ectraction recovery vs.
[30,50]. The results for nortriptyline is presented in Fig. 4a, and applied voltage for extraction time 30 min.
the results reinforced the theoretical model. When the applied
voltage is 40 V, the extraction recovery increases fast with increas-
ing time due to the high flux of target analytes across the SLM. The 10 mM HCl was extracted as described above. Four various temper-
result for 10 V was similar, but in this case, the flux over the SLM atures (5 °C = 278:15 K, 10 °C = 283:15 K, 25 °C = 298:15 K, and
was much lower, and the flux remained reasonably constant 40 °C = 13:15 K) were selected, and extraction recovery in terms
throughout the 10 min extraction period. Flux was lower even at of time plot was obtained for each of the temperatures. The impact
5 V, primarily for nortriptyline. According to the theoretical model of extraction temperature on drug species is illustrated in Fig. 6.
in this study and the practical experiments, high voltages are During the first 5 min of extraction at 40 °C, the flux was high,
needed for rapid extraction under the conditions described [51]. and the system reached steady-state after approximately 5 min.
All drugs have shown an increase in flux with increased volt- Whenever the temperature was reduced, the initial flux would
ages. As seen in Fig. 4b, a slight decrease in the extraction recovery decrease, and the steady-state would require an extended period
was visited when the voltage reached 35 V. This is not surprising of time. According to the experimental results, the negative tem-
because it was likely generated by drug back extraction into the perature effect on the system’s dimensionless driving force was
SLM and donor phase as pH increased slightly in the acceptor less significant than the positive temperature effect on the diffu-
phase electrolysis. Consequently, low voltages can decrease the sion coefficient.
extraction recovery because they generate a weak electric field, According to the Fig. 6b, the recovery of all drug compounds
but too high voltages also have an adverse effect due to fluctua- increased proportionally with the increasing extraction tempera-
tions and bubble creation difficulties. ture, achieving maximum values at 313:15 K. In addition, a high
Temperature is another parameter affecting the performance of temperature can also affect flux by altering partition coefficients
the extraction process. Basically, the system’s driving force is and the practical effect of temperature on flux. The study found
decreased with increasing temperature, but the condition is com- that temperatures slightly above room temperature may maximize
plex because the diffusion coefficient is temperature-dependent, extraction rate under the conditions operated in this study, how-
and this value improves with increasing temperature. In order to ever, temperatures exceeding 313:15 K may lead to partial degra-
study this matter, simulations were run in the following way; a dation of the SLM.
donor phase consisting of five drug species (Fig. 2a) located in

6
M. Khosravikia and A. Rahbar-Kelishami Journal of Molecular Liquids 358 (2022) 119210

Fig. 6. (a) Extraction recovery vs. extraction time for nortriptyline at different
temperatures, and 10 mM HCl in the acceptor solution, and (b) extraction recovery
vs. temperatures for extraction time 30 min.

During an EME process, charged analytes are transported via

organic SLMs from an aqueous donor phase into an acceptor phase.
It is possible to adjust the pH value of the donor solution in order to
obtain an ionic form of the target analytes. To this end, in experi-
mental works, the donor phase containing the analyte is diluted
with acidic/basic solutions such as HCl or NaOH to achieve pH val-
ues within the range of 1:0  14:0 [59]. It should be noted that dif-
ferent pH values change the charge of the drug species, so in
proportion to each pH, the extraction recovery rate is unique.
Fig. 7a shows the extraction recovery changes over time for differ-
ent pH values of the donor phase at constant pH for the acceptor
phase. As mentioned earlier, the driving force of mass transfer of
charged species is increased with increasing voltage, which leads
to increased recovery. On the other hand, at pHd ¼ 2, all drugs
show hydrophilic behaviour, so they tend to enter the acceptor
phase. Therefore, the most elevated extraction recovery was con- Fig. 7. Extraction recovery vs. extraction time for nortriptyline at 10 mM HCl in the
ducted at pHd ¼ 2:0 and Vapp ¼ 30 V. Electric current and bubble acceptor solution, and different pH (a) donor phases, (b) acceptor phases, and (c)
extraction recovery vs. pH donor phase for extraction time 30 min.
innovation boost with acidity due to the related reduction in Hþ .
The high thickness of organic solvent between the acceptor and
donor phase might cause a decrease in electric current and bobble the acceptor solution pH was studied in 2:0  7:0. The extraction
creation. recoveries are displayed in Fig. 7b. The maximum extraction recov-
It has been demonstrated that variation of pH value in the ery was achieved at pH ¼ 2:0. It seems that the ion exchange pro-
acceptor phase can affect the EME recovery [31]. In this work,
7
M. Khosravikia and A. Rahbar-Kelishami
cess has less efficiency in acidic pH values, and it decreases with
the rise of pH in the acceptor solution.
From another point of view, Fig. 7c shows the effect of donor
phase pH on extraction recovery. As previously shown in Fig. 2b,
the charge of a drug species is sensitive to pH changes; that is,
by increasing the pH from the acidic region to the base, the surface
charge of any drug charges according to the distribution of hydro-
gen ions. As a result, it can be claimed that to maintain the extrac-
tion recovery during the EME process, it is better to maintain the
pH in the acidic range, and also at higher voltages, the process effi-
ciency is higher.
In Fig. 8a, the ionic diffusion coefficient is analyzed in relation to
the expected extraction recovery. This parameter appears to have
more significance in the simulation. When the diffusion coefficient
is smaller, the recovery for all drugs is reduced significantly.
Amplification or decreases of this parameter, which is involved in
both diffusion and migration terms in the Nernst-Planck equation,
affect the extraction process in a profound way.
EME offers the advantage of being able to control the thickness
of the three phases with great precision by loading different quan-
tities of respective solutions into the setup, such as donor, SLM, and
Fig. 8. Extraction recovery vs. extraction time for nortriptyline (a) at different
diffusion coefficient and applied voltage, in 10 mM HCl in the acceptor solution, and
(b) at different SLM thickness in 10 mM HCl in the acceptor solution.
8
Journal of Molecular Liquids 358 (2022) 119210
acceptor. SLM thickness and, therefore, the distance across which
the analyte ions must be transferred determines the volume of
organic solvent aspirated into the unit during EME. For this inves-
tigation, the minimum thickness of SLM was set at 200 lm, and
three other thickness increments of 100 lm were also tested. With
decreasing SLM thickness, extraction efficiency increased, where
the maximum extraction yield was achieved with 200 lm of
SLM. Consequently, thicker membranes resulted in significantly
lower drug transfer since the resistance of organic membranes
determines the electrical current of the EME system. As shown in
Fig. 8b, different thicknesses of SLM result in varying EME for drug
extraction. EME’s conductivity increases in proportion to the thick-
ness of the organic layer between the donor and acceptor solutions.
An increase in the electrical field, which results in an increase in
extraction efficiency, occurred when a constant voltage was used.
5. Conclusions
The system discussed here consists of either EME setup, i.e.
donor, SLM, and acceptor, connecting two cylindrical tanks con-
taining aqueous solutions. A mathematical model of electromem-
brane extraction was presented in this paper. We calculated the
ionic concentrations of the species and the electric potential distri-
butions for a 2D field of a donor, organic SLM, and acceptor phases
using coupled Nernst-Planck-Poisson equations under the required
boundary conditions associated with the problem. Poisson-Nernst-
Planck equations were simultaneously solved by means of the
finite element method, and simulated data were evaluated. Using
the suggested model, experimental results in the literature were
successfully reproduced in a qualitative manner. Initially, we con-
sidered similar properties in hollow fiber membrane and donor/ac-
ceptor solution to solve the governing equations. In the next step,
the effect of parameters such as applied voltage, pH donor/acceptor
phase, membrane thickness, initial drug concentration, extraction
time, the diffusion coefficient of the drug species and membrane
porosity on the performance of electromembrane extraction were
studied by applying partitioning conditions. The main results of
the current research, which for the first time reports the drug
extraction of the EME method, are as follows:
(a) The diffusion coefficients in the SLM decrease with an
increased concentration of analyte ions. Thus, with contin-
ued processing, the membrane’s efficiency will decrease.
(b) As the porosity to tortuosity ratio increases, the membrane
permeability decreases as a result of the extraction
efficiency.
(c) EME has less extraction time than its counterparts, which
means it has a shorter equilibrium time, which is helpful
in terms of energy and cost.
(d) Low voltages can decrease the extraction recovery because
they generate a weak electric field, but too high voltages also
have an adverse effect due to fluctuations and bubble cre-
ation difficulties.
(e) Increasing the temperature can have two different effects;
first, as the temperature increases, the diffusion coefficient
increases, which leads to improved recovery. However, on
the other hand, increasing the temperature leads to the
destruction of SLM.
(f) It should be noted that different pH values change the
charge of the drug species, so in proportion to each pH, the
extraction recovery rate is unique.
(g) When the diffusion coefficient is smaller, the recovery for all
drugs is reduced significantly.
M. Khosravikia and A. Rahbar-Kelishami
(h) Thicker membranes resulted in significantly lower drug
transfer since the resistance of organic membranes determi-
nes the electrical current of the EME system.
CRediT authorship contribution statement
Mohammad Khosravikia: Conceptualization, Methodology,
Validation, Writing – original draft. Ahmad Rahbar-Kelishami:
Methodology, Writing – review & editing, Supervision, Project
administration.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
The research council at Iran University of Science and Technol-
ogy (IUST) is highly appreciated for its financial support during this
research.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molliq.2022.119210.
References
[1] A.A. Hassan, A. Tanimu, K. Alhooshani, J. Mol. Liq. 336 (2021) 116370, https://
doi.org/10.1016/j.molliq.2021.116370.
[2] A. Ismailzadeh, M. Masrournia, Z. Es’haghi, M.R. Bozorgmehr, J. Mol. Liq. 317
(2020) 113979, https://doi.org/10.1016/j.molliq.2020.113979.
[3] S. Huber, M. Harder, N. Weidacher, K. Erharter, C. Kreutz, H. Schottenberger, G.
K. Bonn, M. Rainer, J. Mol. Liq. 343 (2021) 117669, https://doi.org/10.1016/
j.molliq.2021.117669.
[4] M.R. Siddiqui, Z.A. AlOthman, N. Rahman, Arabian J. Chem. 10 (2017) S1409,
https://doi.org/10.1016/j.arabjc.2013.04.016.
[5] D.M. Pavlović, S. Babić, A.J. Horvat, M. Kaštelan-Macan, TrAC, Trends Anal.
Chem. 26 (2007) 1062, https://doi.org/10.1016/j.trac.2007.09.010.
[6] A. Alinezhad, M. Khatibi, S. Nezameddin Ashrafizadeh, J. Mol. Liq. 347 (2022)
118324, https://doi.org/10.1016/j.molliq.2021.118324.
[7] M. Zheng, C. Zhang, L. Wang, K. Wang, W. Kang, K. Lian, H. Li, Microchem. J. 160
(2021) 105647, https://doi.org/10.1016/j.microc.2020.105647.
[8] X. Fu, Y. Liao, H. Liu, Anal. Bioanal. Chem. 381 (2005) 75, https://doi.org/
10.1016/j.trac.2007.09.010.
[9] N. Drouin, P. Kubáň, S. Rudaz, S. Pedersen-Bjergaard, J. Schappler, TrAC, Trends
Anal. Chem. 113 (2019) 357, https://doi.org/10.1016/j.trac.2018.10.024.
[10] A.R. Fakhari, S. Asadi, H.M. Kosalar, A. Sahragard, A. Hashemzadeh, M.M. Amini,
Anal. Methods 9 (2017) 5646, https://doi.org/10.1039/C7AY01093A.
[11] M.I.G.S. Almeida, R.W. Cattrall, S.D. Kolev, Anal. Chim. Acta 987 (2017) 1,
https://doi.org/10.1016/j.aca.2017.07.032.
[12] F.A. Hansen, E. Santigosa-Murillo, M. Ramos-Payán, M. Muñoz, E. Leere
Øiestad, S. Pedersen-Bjergaard, Anal. Chim. Acta 1143 (2021), https://doi.org/
10.1016/j.aca.2020.11.044.
[13] F. Yang, K. Ma, Y. Cao, C. Ni, RSC Adv. 11 (2021) 19874, https://doi.org/10.1039/
D1RA01530C.
[14] I. Vasconcelos, C. Fernandes, TrAC Trends Anal. Chem. 89 (2017) 41, https://
doi.org/10.1016/j.trac.2016.11.011.
[15] N.J. Simpson, Solid-Phase Extraction: Principles, Techniques, and Applications,
CRC Press, 2000.
[16] C.L. Arthur, J. Pawliszyn, Anal. Chem. 62 (1990) 2145, https://doi.org/10.1021/
ac00218a019.
[17] L. Su, N. Zhang, J. Tang, L. Zhang, X. Wu, Anal. Chim. Acta 1186 (2021) 339120,
https://doi.org/10.1016/j.aca.2021.339120.
[18] K.S. Roy, E. Nazdrajić, O.I. Shimelis, M.J. Ross, Y. Chen, H. Cramer, J. Pawliszyn,
Analytical Chemistry 93 (2021) 11061, doi:10.1021/acs.analchem.1c01986.
[19] H. Lord, J. Pawliszyn, J. Chromatogr. A 902 (2000) 17, https://doi.org/10.1016/
S0021-9673(00)00836-0.
[20] A. Jain, K.K. Verma, Anal. Chim. Acta 706 (2011) 37, https://doi.org/10.1016/j.
aca.2011.08.022.
Journal of Molecular Liquids 358 (2022) 119210
[21] S.K. Kailasa, J.R. Koduru, T.J. Park, R.K. Singhal, H.-F. Wu, Trends Environ. Anal.
Chem. 29 (2021) e00113, https://doi.org/10.1016/j.teac.2020.e00113.
[22] E. Abdollahi, A. Heidari, T. Mohammadi, A.A. Asadi, M.A. Tofighy, Separ. Purif.
Technol. 257 (2021) 117931, https://doi.org/10.1016/j.seppur.2020.117931.
[23] L. Meng, W. Zhang, P. Meng, B. Zhu, K. Zheng, J. Chromatogr. B 989 (2015) 46,
https://doi.org/10.1016/j.jchromb.2015.02.039.
[24] K.M. Al Azzam, A. Makahleah, B. Saad, S.M. Mansor, J. Chromatogr. A 3654
(2010) 1217, https://doi.org/10.1016/j.chroma.2010.03.055.
[25] M. Valcárcel, S. Cárdenas, R. Lucena, Springer, 2014.
[26] A. Sarafraz-Yazdi, A. Amiri, TrAC Trends Anal. Chem. 29 (2010) 1, https://doi.
org/10.1016/j.trac.2009.10.003.
[27] J. Lee, H.K. Lee, K.E. Rasmussen, S. Pedersen-Bjergaard, Anal. Chim. Acta 624
(2008) 253, https://doi.org/10.1016/j.aca.2008.06.050.
[28] W.A. Khan, M.B. Arain, Y. Yamini, N. Shah, T.G. Kazi, S. Pedersen-Bjergaard, M.
Tajik, J. Pharm. Anal. 10 (2020) 109, https://doi.org/10.1016/j.
jpha.2019.12.003.
[29] M. Khatibi, A. Sadeghi, S.N. Ashrafizadeh, PCCP 23 (2021) 2211, https://doi.org/
10.1039/D0CP05974A.
[30] A. Gjelstad, S. Pedersen-Bjergaard, Anal. Methods 5 (2013) 4549, https://doi.
org/10.1039/C3AY40547H.
[31] Y. Yamini, S. Seidi, M. Rezazadeh, Anal. Chim. Acta 814 (2014) 1, https://doi.
org/10.1016/j.aca.2013.12.019.
[32] C. Huang, Z. Chen, A. Gjelstad, S. Pedersen-Bjergaard, X. Shen, TrAC Trends
Anal. Chem. 95 (2017) 47, https://doi.org/10.1016/j.trac.2017.07.027.
[33] S. Pedersen-Bjergaard, C. Huang, A. Gjelstad, J. Pharm. Anal. 7 (2017) 141,
https://doi.org/10.1016/j.jpha.2017.04.002.
[34] M. Amini, A. Rahbar-Kelishami, M. Alipour, O. Vahidi, J. Membr. Sci. Res. 4
(2018) 121. http://10.22079/jmsr.2017.63968.1138.
[35] M. Khatibi, S.N. Ashrafizadeh, A. Sadeghi, Anal. Chim. Acta 1122 (2020) 48,
https://doi.org/10.1016/j.aca.2020.05.011.
[36] S.-R. Wang, S. Wang, J. Food Drug Anal. 22 (2014) 418, https://doi.org/10.1016/
j.jfda.2014.03.006.
[37] T.M. Middelthon-Bruer, A. Gjelstad, K.E. Rasmussen, S. Pedersen-Bjergaard, J.
Sep. Sci. 31 (2008) 753, https://doi.org/10.1002/jssc.200700502.
[38] E. Santigosa-Murillo, S. Maspoch, M. Muñoz, M. Ramos-Payán, Anal. Chim. Acta
1160 (2021) 338448, https://doi.org/10.1016/j.aca.2021.338448.
[39] P. Kubáň, L. Strieglerová, P. Gebauer, P. Boček, Electrophoresis 32 (2011) 1025,
https://doi.org/10.1002/elps.201000462.
[40] T.Y. Tan, C. Basheer, K.P. Ng, H.K. Lee, Anal. Chim. Acta 739 (2012) 31, https://
doi.org/10.1016/j.aca.2012.06.007.
[41] M. Khatibi, S.N. Ashrafizadeh, A. Sadeghi, Electrochim. Acta 395 (2021)
139221, https://doi.org/10.1016/j.electacta.2021.139221.
[42] S. Pedersen-Bjergaard, K.E. Rasmussen, J. Chromatogr. A 1109 (2006) 183,
https://doi.org/10.1016/j.chroma.2006.01.025.
[43] X. Yu, X. Li, S. You, Y. Shi, R. Zhu, Y. Dong, C. Huang, J. Chromatogr. A 1629
(2020) 461480, https://doi.org/10.1016/j.chroma.2020.461480.
[44] A. Rahimi, S. Nojavan, M. Maghsoudi, Microchem. J. 157 (2020) 105001,
https://doi.org/10.1016/j.microc.2020.105001.
[45] H.B. Piskáčková, P. Kollárová-Brázdová, R. Kučera, M. Macháček, S. Pedersen-
Bjergaard, P. Štěrbová-Kovaříková, Anal. Chim. Acta (2021) 338742, https://
doi.org/10.1016/j.aca.2021.338742.
[46] M. Behpour, H. Tabani, S. Nojavan, J. Chromatogr. B 1152 (2020) 122258,
https://doi.org/10.1016/j.jchromb.2020.122258.
[47] S. Ayoubi, M. Khatibi, S.N. Ashrafizadeh, Microfluid. Nanofluid. 25 (2021) 1,
https://doi.org/10.1007/s10404-021-02501-3.
[48] M. Karimzadeh, M. Khatibi, S.N. Ashrafizadeh, Int. Commun. Heat Mass
Transfer 129 (2021) 105728, https://doi.org/10.1016/j.
icheatmasstransfer.2021.105728.
[49] M. Karimzadeh, Z. Seifollahi, M. Khatibi, S.N. Ashrafizadeh, Electrochim. Acta
399 (2021) 139376, https://doi.org/10.1016/j.electacta.2021.139376.
[50] A. Gjelstad, K.E. Rasmussen, S. Pedersen-Bjergaard, J. Chromatogr. A 1174
(2007) 104, https://doi.org/10.1016/j.chroma.2007.08.057.
[51] A. Gjelstad, H. Jensen, K.E. Rasmussen, S. Pedersen-Bjergaard, Anal. Chim. Acta
742 (2012) 10, https://doi.org/10.1016/j.aca.2011.12.039.
[52] F. Hansen, F. Jaghl, E.L. Øiestad, H. Jensen, S. Pedersen-Bjergaard, C. Huang,
Anal. Chim. Acta 1124 (2020) 129, https://doi.org/10.1016/j.aca.2020.05.039.
[53] M.S. Restan, S.B. Ramsrud, H. Jensen, S. Pedersen-Bjergaard, J. Sep. Sci. 43
(2020) 3120, https://doi.org/10.1002/jssc.202000391.
[54] K.F. Seip, H. Jensen, M.H. Sønsteby, A. Gjelstad, S. Pedersen-Bjergaard,
Electrophoresis 34 (2013) 792, https://doi.org/10.1002/elps.201200587.
[55] C. Huang, X. Shen, A. Gjelstad, S. Pedersen-Bjergaard, J. Membr. Sci. 548 (2018)
176, https://doi.org/10.1016/j.memsci.2017.11.001.
[56] in: M.L. Bruschi (Ed.) Strategies to Modify the Drug Release from
Pharmaceutical Systems, Woodhead Publishing, 2015, p. 37–62.
[57] F. Fadaei, S. Shirazian, S.N. Ashrafizadeh, Desalination 275 (2011) 126, https://
doi.org/10.1016/j.desal.2011.02.039.
[58] B. Mohammad Tehrani, A. Rahbar-Kelishami, Chem. Eng. Process. – Process
Intens. 143 (2019) 107625, doi:10.1016/j.cep.2019.107625.
[59] M. Pinelo, J. Sineiro, M.A.J. Núñez, J. Food Eng. 77 (2006) 57. doi:10.1016/j.
jfoodeng.2005.06.021.